Role of anti-SARS-CoV T cell response in pathogenesis

描述（由申请人提供）：与年轻人群相比，许多病毒感染在老年人中更为严重。2002-2003年爆发的严重急性呼吸系统综合征（SARS）突出地说明了这一点，其中超过50%的60岁以上的患者死亡，而24岁以下的患者没有死亡。在感染了小鼠适应的SARS冠状病毒株（SARS-CoV）的小鼠中也观察到了几乎相同的敏感性的急剧年龄依赖性，这使得这成为识别老年小鼠中宿主免疫反应缺陷的有用模型。我们的初步研究结果表明，呼吸道树突状细胞（rDC）的迁移到引流淋巴结（DLN）是有缺陷的，在老年SARS-CoV感染的小鼠，导致抗病毒T细胞反应差，病毒清除差，肺损伤增加，以及死亡率增加。用poly I：C预处理逆转了在这些老年感染小鼠中观察到的发病率和死亡率增加。该建议的中心假设是，rDC功能和随后的T细胞应答的年龄依赖性变化对于在患有呼吸道病毒感染的老年人群中观察到的不良结局至关重要。将通过以下具体目标来实现这一目标。目标1.确定SARS-CoV感染的12- 14 m小鼠中T细胞应答缺陷的程度是T细胞内在的。rDC迁移至DLN的缺陷抑制了稳健的T细胞应答的产生，但该观察结果并不排除导致严重疾病的额外的T细胞内在缺陷。将调查这种可能性。目标二。探讨老年小鼠rDC功能障碍的发生基础和时间。本研究的目的是确定在SARS-CoV感染的老年小鼠中是否存在rDC功能的其他缺陷，并确定这些缺陷的基础。将研究具有保护作用的poly I：C的作用机制。最后，将分析特定脂质介质（如前列腺素E2）功能的年龄依赖性变化，这些介质对rDC有效迁移至DLN至关重要。目标3：确定rDC功能缺陷是否在呼吸道病原体感染的老年小鼠中常见。该提案的一个关键目标是通过确定rDC功能和随后的抗病毒T细胞反应是否在感染其他呼吸道病毒的小鼠中受损来检查我们结果的一般性，所述其他呼吸道病毒例如甲型流感病毒、呼吸道合胞病毒或MHV-1（一种嗜肺性鼠冠状病毒）。将rDC缺陷鉴定为对病毒性呼吸道感染易感性增加的关键，将为感染患者提供新的治疗靶点。

DESCRIPTION (provided by applicant): Many viral infections are more severe in aged compared to young populations. This was strikingly illustrated in the 2002-2003 outbreak of the Severe Acute Respiratory Syndrome (SARS), in which >50% of patients who were over 60 year old died while no deaths occurred in those under 24 years. A nearly identical steep age dependence in susceptibility is also observed in mice infected with mouse-adapted strains of SARS-coronavirus (SARS-CoV), making this a useful model for identifying defects in the host immune response in aged mice. Our preliminary results suggest that migration of respiratory dendritic cells (rDC) to draining lymph nodes (DLN) is defective in aged SARS-CoV-infected mice, resulting in a poor anti-virus T cell response, poor virus clearance and increased lung damage as well as increased mortality. Pre-treatment with poly I:C reverses the increased morbidity and mortality observed in these aged infected mice. The central hypothesis of this proposal is that age-dependent changes in rDC function and subsequent T cell responses are critical for the poor outcomes observed in aged populations with respiratory virus infections. This objective will be approached in the following specific aims. Aim 1. To determine the extent to which the defective T cell response in SARS-CoV- infected 12-14m mice is T cell-intrinsic. Defects in rDC migration to the DLN inhibit the generation of a robust T cell response, but this observation does not preclude additional T cell- intrinsic defects contributing to severe disease. This possibility will be investigated. Aim 2. To investigate the basis and time of onset of rDC dysfunction in old mice. The goals of this aim will be to determine if additional defects in rDC function exist in SARS-CoV-infected aged mice and determine the basis of these defects. The mechanism of action of poly I:C, which is protective, will be investigated. Finally, age-dependent changes in the function of specific lipid mediators such as prostaglandin E2, which are critical for efficient rDC migration to DLN, will be analyzed. Aim 3. To determine whether defective rDC function is common in aged mice infected with respiratory pathogens. A key goal of the proposal is to examine the generality of our results by determining whether rDC function and consequent anti-virus T cell responses are compromised in mice infected with other respiratory viruses, such as influenza A virus, respiratory syncytial virus or MHV-1, a pneumotropic murine coronavirus. Identification of rDC defects as critical in the increased susceptibility to viral respiratory infections will provide a novel therapeutic target in infected patients.